Humans and other mammals have a constant and absolute requirement for oxygen and tissue oxygenation is maintained within a narrow range. In many disease states, however, oxygen homeostasis is disrupted and hypoxia/ischemia is an important factor contributing to the pathophysiology of ischemic cardiovascular disease, chronic lung disease, and other major causes of mortality. The broad, long-term goal of the proposed research is to increase our understanding of the role of the transcriptional regulator hypoxia-inducible factor 1 (HIF-1) in the maintenance of oxygen homeostasis. In particular, the studies that will be performed in years 10-14 of R01HL55338 will focus on the role of HIF-1 as a master regulator of tissue vascularization. The knowledge gained from the proposed experiments will be relevant to the treatment of disorders associated with altered vascularization, particularly ischemic cardiovascular disease. The specific aims are: 1. To determine the role of HIF-1 in the vascular response to tissue ischemia. We will test the hypothesis that HIF-1 activity within ischemic muscle promotes angiogenic growth factor gene expression and vascularization. 2. To investigate the role of HlF-1 in vascular progenitor cells. We will test the hypothesis that HIF-1 activity in endothelial progenitor cells (EPCs) promotes their differentiation, recruitment, and survival, and stimulates EPC-mediated vascular remodeling in ischemic tissue. To delineate transcriptional networks regulated by HIF-1 in human arterial endothelial and smooth muscle cells. We will test the hypothesis that HIF-1 controls the expression of distinct batteries of genes in a cell type- specific manner and that this regulation is mediated via either direct DMA binding or indirectly via the regulation of other transcription factors.